间充质干细胞治疗自身免疫性肝病的临床研究进展

史婉婉; 钱建丹; 王贵强

doi:10.3969/j.issn.1001-5256.2023.05.002

间充质干细胞治疗自身免疫性肝病的临床研究进展

DOI: 10.3969/j.issn.1001-5256.2023.05.002

北京大学第一医院感染疾病科，北京 100034

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：史婉婉负责撰写文章及修订论文; 钱建丹负责审阅并修订论文；王贵强负责提出研究选题和终审论文。

详细信息

通信作者:
王贵强，john131212@sina.com (ORCID: 0000-0003-0515-7974)

计量
- 文章访问数: 466
- HTML全文浏览量: 92
- PDF下载量: 124
- 被引次数: 0
出版历程
- 收稿日期: 2023-03-14
- 录用日期: 2023-04-11
- 出版日期: 2023-05-20

Clinical research advances in mesenchymal stem cells for the treatment of autoimmune liver diseases

Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China

More Information

Corresponding author: WANG Guiqiang, john131212@sina.com (ORCID: 0000-0003-0515-7974)

摘要

摘要: 自身免疫性肝病因治疗选择和方式比较局限，因此迫切需要寻求新的治疗方法。间充质干细胞(MSC)作为干细胞治疗最常见的细胞来源，在调节先天和适应性免疫反应中发挥着重要作用，已广泛应用于临床试验，治疗自身免疫性疾病和炎症性疾病。最近的实验和临床研究表明，MSC及MSC-EV可以抑制肝脏多种促炎细胞的激活和增殖，如Th1、Th17和M1巨噬细胞，调节T淋巴细胞和B淋巴细胞不同亚群的分化，减少促炎细胞因子的分泌，同时促进抗炎细胞的增殖，从而发挥免疫调节作用。本文就MSC以及MSC-EV在自身免疫性肝病治疗方面的临床试验，及其免疫调节作用和促进肝细胞再生等机制进行综述，并简要概述了MSC以及MSC-EV在临床应用中的潜在用途和局限性。
- 肝炎, 自身免疫性 /
- 原发性胆汁性胆管炎 /
- 原发性硬化性胆管炎 /
- 间质干细胞
Abstract: Due to limited options and modalities for the etiological treatment of autoimmune liver diseases, it is urgent to seek new therapeutic methods for liver autoimmune diseases. As the most common source of cells for stem cell therapy, mesenchymal stem cells (MSCs) play an important role in regulating innate and adaptive immune responses and have been widely used in clinical trials for the treatment of autoimmune diseases and inflammatory diseases. Recent experimental and clinical studies have shown that MSCs and MSC-EVs can inhibit the activation and proliferation of a variety of liver proinflammatory cells (such as Th1, Th17, and M1 macrophages), regulate the differentiation of different subsets of T and B cells, reduce the secretion of proinflammatory cytokines, and promote the proliferation of anti-inflammatory cells, thereby playing an immunoregulatory role. This article reviews the clinical trials of MSCs and MSC-EVs in the treatment of autoimmune liver diseases and their mechanism in regulating immune function and promoting hepatocyte regeneration and briefly describes the potential application and limitations of MSCs and MSC-EVs in clinical practice.
- Hepatitis, Autoimmune /
- Primary Biliary Cholangitis /
- Primary Sclerosing Cholangitis /
- Mesenchymal Stem Cells

HTML全文

参考文献(54)

[1]	RONCA V, MANCUSO C, MILANI C, et al. Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis[J]. J Leukoc Biol, 2020, 108(2): 659-671. DOI: 10.1002/JLB.5MR0320-200R.
[2]	LONGHI MS. Lactobacillus reuteri joins the liver autoimmune arena[J]. Cell Host Microbe, 2022, 30(7): 901-903. DOI: 10.1016/j.chom.2022.06.004.
[3]	GULAMHUSEIN AF, HIRSCHFIELD GM. Primary biliary cholangitis: pathogenesis and therapeutic opportunities[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(2): 93-110. DOI: 10.1038/s41575-019-0226-7.
[4]	LEE CW, CHEN YF, WU HH, et al. Historical perspectives and advances in mesenchymal stem cell research for the treatment of liver diseases[J]. Gastroenterology, 2018, 154(1): 46-56. DOI: 10.1053/j.gastro.2017.09.049.
[5]	FRIEDENSTEIN AJ, PETRAKOVA KV, KUROLESOVA AI, et al. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues[J]. Transplantation, 1968, 6(2): 230-247.
[6]	HASHMI S, AHMED M, MURAD MH, et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis[J]. Lancet Haematol, 2016, 3(1): e45-52. DOI: 10.1016/S2352-3026(15)00224-0.
[7]	FUJⅡ S, MIURA Y. Immunomodulatory and regenerative effects of MSC-derived extracellular vesicles to treat acute GVHD[J]. Stem Cells, 2022, 40(11): 977-990. DOI: 10.1093/stmcls/sxac057.
[8]	WONG SK, BLUM SM, SUN X, et al. Efficacy and safety of immune checkpoint inhibitors in young adults with metastatic melanoma[J]. Eur J Cancer, 2023, 181: 188-197. DOI: 10.1016/j.ejca.2022.12.013.
[9]	LEE E, EPANOMERITAKIS IE, LU V, et al. Bone marrow-derived mesenchymal stem cell implants for the treatment of focal chondral defects of the knee in animal models: a systematic review and meta-analysis[J]. Int J Mol Sci, 2023, 24(4) : 3227. DOI: 10.3390/ijms24043227.
[10]	DU F, LIU M, WANG J, et al. Metformin coordinates with mesenchymal cells to promote VEGF-mediated angiogenesis in diabetic wound healing through Akt/mTOR activation[J]. Metabolism, 2023, 140: 155398. DOI: 10.1016/j.metabol.2023.155398.
[11]	QIN L, LIU N, BAO CL, et al. Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin[J]. Acta Pharmacol Sin, 2023, 44(2): 268-287. DOI: 10.1038/s41401-022-00952-0.
[12]	KERKAR N, CHAN A. Autoimmune hepatitis, sclerosing cholangitis, and autoimmune sclerosing cholangitis or o verlap syndrome[J]. Clin Liver Dis, 2018, 22(4): 689-702. DOI: 10.1016/j.cld.2018.06.005.
[13]	LIBERAL R, GRANT CR, LONGHI MS, et al. Diagnostic criteria of autoimmune hepatitis[J]. Autoimmun Rev, 2014, 13(4-5): 435-440. DOI: 10.1016/j.autrev.2013.11.009.
[14]	TRIVEDI PJ, HUBSCHER SG, HENEGHAN M, et al. Grand round: Autoimmune hepatitis[J]. J Hepatol, 2019, 70(4): 773-784. DOI: 10.1016/j.jhep.2018.11.006.
[15]	L VOLK M, REAU N. Diagnosis and management of autoimmune hepatitis in adults and children: a patient-friendly summary of the 2019 AASLD guidelines[J]. Clin Liver Dis (Hoboken), 2021, 17(2): 85-89. DOI: 10.1002/cld.1080.
[16]	LOHSE AW, SEBODE M, JØRGENSEN MH, et al. Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group[J]. J Hepatol, 2020, 73(6): 1496-1506. DOI: 10.1016/j.jhep.2020.07.023.
[17]	HORWICH BH, HAN H. Diagnosis and treatment of primary biliary cholangitis: A patient-friendly summary of the 2018 AASLD practice guidance[J]. Clin Liver Dis (Hoboken), 2021, 18(5): 255-259. DOI: 10.1002/cld.1158.
[18]	SHAH RA, KOWDLEY KV. Current and potential treatments for primary biliary cholangitis[J]. Lancet Gastroenterol Hepatol, 2020, 5(3): 306-315. DOI: 10.1016/S2468-1253(19)30343-7.
[19]	WANG L, LI J, LIU H, et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis[J]. J Gastroenterol Hepatol, 2013, 28 Suppl 1: 85-92. DOI: 10.1111/jgh.12029.
[20]	WANG L, HAN Q, CHEN H, et al. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis[J]. Stem Cells Dev, 2014, 23(20): 2482-2489. DOI: 10.1089/scd.2013.0500.
[21]	LINDKVIST B, BENITO DE VALLE M, GULLBERG B, et al. Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden[J]. Hepatology, 2010, 52(2): 571-577. DOI: 10.1002/hep.23678.
[22]	MODHA K, NAVANEETHAN U. Diagnosis and management of primary sclerosing cholangitis-perspectives from a therapeutic endoscopist[J]. World J Hepatol, 2015, 7(5): 799-805. DOI: 10.4254/wjh.v7.i5.799.
[23]	JADLOWIEC CC, TANER T. Liver transplantation: Current status and challenges[J]. World J Gastroenterol, 2016, 22(18): 4438-4445. DOI: 10.3748/wjg.v22.i18.4438.
[24]	HU C, ZHAO L, DUAN J, et al. Strategies to improve the efficiency of mesenchymal stem cell transplantation for reversal of liver fibrosis[J]. J Cell Mol Med, 2019, 23(3): 1657-1670. DOI: 10.1111/jcmm.14115.
[25]	RAPOSO G, STOORVOGEL W. Extracellular vesicles: exosomes, microvesicles, and friends[J]. J Cell Biol, 2013, 200(4): 373-383. DOI: 10.1083/jcb.201211138.
[26]	HE C, YANG Y, ZHENG K, et al. Mesenchymal stem cell-based treatment in autoimmune liver diseases: underlying roles, advantages and challenges[J]. Ther Adv Chronic Dis, 2021, 12: 2040622321993442. DOI: 10.1177/2040622321993442.
[27]	LO SICCO C, REVERBERI D, BALBI C, et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization[J]. Stem Cells Transl Med, 2017, 6(3): 1018-1028. DOI: 10.1002/sctm.16-0363.
[28]	DUFFY MM, RITTER T, CEREDIG R, et al. Mesenchymal stem cell effects on T-cell effector pathways[J]. Stem Cell Res Ther, 2011, 2(4): 34. DOI: 10.1186/scrt75.
[29]	KHARE D, OR R, RESNICK I, et al. Mesenchymal stromal cell-derived exosomes affect mrna expression and function of B-lymphocytes[J]. Front Immunol, 2018, 9: 3053. DOI: 10.3389/fimmu.2018.03053.
[30]	SU J, CHEN X, HUANG Y, et al. Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species[J]. Cell Death Differ, 2014, 21(3): 388-396. DOI: 10.1038/cdd.2013.149.
[31]	CHABANNES D, HILL M, MERIEAU E, et al. A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells[J]. Blood, 2007, 110(10): 3691-3694. DOI: 10.1182/blood-2007-02-075481.
[32]	NÉMETH K, LEELAHAVANICHKUL A, YUEN PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production[J]. Nat Med, 2009, 15(1): 42-49. DOI: 10.1038/nm.1905.
[33]	CHEN D, TANG P, LIU L, et al. Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway[J]. Cell Cycle, 2018, 17(7): 858-867. DOI: 10.1080/15384101.2018.1442624.
[34]	SIOUD M, MOBERGSLIEN A, BOUDABOUS A, et al. Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation[J]. Scand J Immunol, 2010, 71(4): 267-274. DOI: 10.1111/j.1365-3083.2010.02378.x.
[35]	CHEN QH, WU F, LIU L, et al. Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro[J]. Stem Cell Res Ther, 2020, 11(1): 91. DOI: 10.1186/s13287-020-01612-y.
[36]	DUNN CM, KAMEISHI S, CHO YK, et al. Interferon-gamma primed human clonal mesenchymal stromal cell sheets exhibit enhanced immunosuppressive function[J]. Cells, 2022, 11(23): e202301924. DOI: 10.3390/cells11233738.
[37]	LI M, SUN X, KUANG X, et al. Mesenchymal stem cells suppress CD8+ T cell-mediated activation by suppressing natural killer group 2, member D protein receptor expression and secretion of prostaglandin E2, indoleamine 2, 3-dioxygenase and transforming growth factor-β[J]. Clin Exp Immunol, 2014, 178(3): 516-524. DOI: 10.1111/cei.12423.
[38]	AKIYAMA K, CHEN C, WANG D, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis[J]. Cell Stem Cell, 2012, 10(5): 544-555. DOI: 10.1016/j.stem.2012.03.007.
[39]	LUZ-CRAWFORD P, KURTE M, BRAVO-ALEGRÍA J, et al. Mesenchymal stem cells generate a CD4+CD25+ Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells[J]. Stem Cell Res Ther, 2013, 4(3): 65. DOI: 10.1186/scrt216.
[40]	LIM VY, FENG X, MIAO R, et al. Mature B cells and mesenchymal stem cells control emergency myelopoiesis[J]. Life Sci Alliance, 2023, 6(4): e202301924. DOI: 10.26508/lsa.202301924.
[41]	GARCIA SG, SANDOVAL-HELLÍN N, CLOS-SANSALVADOR M, et al. Mesenchymal stromal cells induced regulatory B cells are enriched in extracellular matrix genes and IL-10 independent modulators[J]. Front Immunol, 2022, 13: 957797. DOI: 10.3389/fimmu.2022.957797.
[42]	RAFEI M, HSIEH J, FORTIER S, et al. Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction[J]. Blood, 2008, 112(13): 4991-4998. DOI: 10.1182/blood-2008-07-166892.
[43]	FRANQUESA M, MENSAH FK, HUIZINGA R, et al. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells[J]. Stem Cells, 2015, 33(3): 880-891. DOI: 10.1002/stem.1881.
[44]	TAMURA R, UEMOTO S, TABATA Y. Immunosuppressive effect of mesenchymal stem cell-derived exosomes on a concanavalin A-induced liver injury model[J]. Inflamm Regen, 2016, 36: 26. DOI: 10.1186/s41232-016-0030-5.
[45]	LU FB, CHEN DZ, CHEN L, et al. Attenuation of experimental autoimmune hepatitis in mice with bone mesenchymal stem cell-derived exosomes carrying MicroRNA-223-3p[J]. Mol Cells, 2019, 42(12): 906-918. DOI: 10.14348/molcells.2019.2283.
[46]	CHEN L, LU FB, CHEN DZ, et al. BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis[J]. Mol Immunol, 2018, 93: 38-46. DOI: 10.1016/j.molimm.2017.11.008.
[47]	SHAO Y, YANG WY, SAAOUD F, et al. IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms[J]. JCI Insight, 2021, 6(19): e152511. DOI: 10.1172/jci.insight.152511.
[48]	WANG W, GUO H, LI H, et al. Interleukin-35 gene- modified mesenchymal stem cells protect concanavalin a-induced fulminant hepatitis by decreasing the interferon gamma level[J]. Hum Gene Ther, 2018, 29(2): 234-241. DOI: 10.1089/hum.2017.171.
[49]	WANG D, ZHANG H, LIANG J, et al. Effect of allogeneic bone marrow-derived mesenchymal stem cells transplantation in a polyI: C-induced primary biliary cirrhosis mouse model[J]. Clin Exp Med, 2011, 11(1): 25-32. DOI: 10.1007/s10238-010-0105-6.
[50]	ZHANG L, MA XJ, FEI YY, et al. Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells[J]. Pharmacol Ther, 2022, 232: 108004. DOI: 10.1016/j.pharmthera.2021.108004.
[51]	NIE H, AN F, MEI J, et al. IL-1β Pretreatment improves the efficacy of mesenchymal stem cells on acute liver failure by enhancing CXCR4 Expression[J]. Stem Cells Int, 2020, 2020: 1498315. DOI: 10.1155/2020/1498315.
[52]	ZHAO Q, REN H, LI X, et al. Differentiation of human umbilical cord mesenchymal stromal cells into low immunogenic hepatocyte-like cells[J]. Cytotherapy, 2009, 11(4): 414-426. DOI: 10.1080/14653240902849754.
[53]	HONCZARENKO M, LE Y, SWIERKOWSKI M, et al. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors[J]. Stem Cells, 2006, 24(4): 1030-1041. DOI: 10.1634/stemcells.2005-0319.
[54]	WANG J, SUN M, LIU W, et al. Stem cell-based therapies for liver diseases: An overview and update[J]. Tissue Eng Regen Med, 2019, 16(2): 107-118. DOI: 10.1007/s13770-019-00178-y.